Selection on mhc: a matter of form over function
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The major histocompatibility complex (MHC) contains the most diverse genes known in vertebrates. High levels of polymorphism are often attributed to pathogen-mediated selection for potential
immune responses to specific parasites or diseases. Surprisingly, however, little empirical evidence exists to support the hypothesis of pathogen-driven selection. Now, new evidence comes
from the study of a small nocturnal lemur living under natural conditions in western Madagascar. In the paper on page 265, by examining neutral microsatellite diversity, MHC-DRB exon 2
polymorphism and parasite burden, Schwensow et al. (2007) found that MHC-DRB genotype is important for resistance to nematode helminths. They conclude that MHC polymorphism is maintained
through pathogen-driven frequency-dependent selection in wild fat-tailed dwarf lemurs (C_heirogaleus medius_). MHC-DRB genes encode proteins that are expressed on the surface of
immunocompetent cells, and critical regions of the protein bind foreign antigens and present them to helper T lymphocytes to activate the immune response. X-ray crystallographic studies of
the three-dimensional structure of MHC-DRB proteins demonstrate that antigen-binding sites vary in conformation, determining the shape of the foreign antigen they bind to. Therefore, it has
been argued that individuals with rare antigen-binding abilities should be more capable of combating diseases, at least in the short term, than individuals with common antigen-binding
capabilities. This rare allele advantage would ultimately promote MHC-DRB polymorphism since pathogens require time to adapt to hosts with rare MHC alleles. So, by the time the pathogen has
adapted to the host, and the previously rare allele has become common in the population, new mutant alleles would have arisen. All but a few rare species exhibit extremely high levels of
MHC-DRB polymorphism. Humans, for example, possess several hundred MHC-DRB alleles. The mechanisms for maintaining such extraordinary MHC polymorphism in humans and other vertebrates have
been hotly debated among immunogeneticists and evolutionary biologists. Within the context of resistance to infectious agents, MHC genetic diversity could be maintained through heterozygote
advantage, frequency-dependent selection or even both. Heterozygote advantage results when an individual with many different MHC alleles responds to a wider array of pathogens than an
individual with less diversity and, consequently, survives to pass on the genes to the next generation. Frequency-dependent selection is the consequence of the aforementioned rare allele
advantage and this explanation appears to be supported by Schwensow et al. (2007) work on fat-tailed dwarf lemurs. The authors distinguished 50 different MHC-DRB exon 2 sequences in a
population of 149 lemurs and reported that individuals possessed between two and four different sequences. This exceptional degree of diversity is notable. However, it also means that
detection of statistically significant associations between parasite burden and specific MHC-DRB sequences would require unfeasibly large sample sizes. To combat the limitation, Schwensow et
al. (2007) pooled their 50 sequences to form 11 supertypes, based on similarities in the predicted antigen-binding sites of the MHC-DRB sequences. Analyses using the 11 supertypes revealed
that one MHC supertype was associated with high intensity and diversity of nematode infections, while another, relatively rare, MHC-supertype was associated with a complete lack of nematode
infection. Contrastingly, overall genome heterozygosity, measured using seven polymorphic microsatellite loci, did not differ between infected and uninfected individuals. Correlations
between specific MHC-DRB sequences and resistance, or susceptibility, to specific pathogens have been reported previously for Atlantic salmon, yellow-necked mice, striped mice, hairy-footed
gerbils and mouse lemurs (reviewed in Piertney and Oliver, 2006). These studies offer support for the frequency-dependent model of pathogen-driven selection. However, direct empirical
demonstration of differential fitness of specific and, most importantly, expressed MHC genotypes in response to pathogens is rare. Only a very small number of studies (Paterson et al., 1998;
Lohm et al., 2002; Penn et al., 2002; Wegner et al., 2003) have had the necessary population size and statistical power to detect subtle effects for expressed MHC gene products and
therefore the debate over the relative importance of pathogen-driven selection continues. Identification of supertypes has proven useful for characterizing the antigen-binding specificities
of common human MHC, also known as the human leukocyte antigen (HLA) types. The grouping of MHC alleles into supertypes is based on common structural and functional features of expressed MHC
genes. In other words, an MHC molecule's form (that is, structure) and function go hand in hand. The connection between an HLA protein's form and function is well understood,
since an HLA-DRB molecule's antigen-binding ability is the consequence of its exon 2 nucleotide sequence. Unfortunately, relatively little is known about the transcription and
expression of MHC-DRB genes in non-human primates, including lemurs, and Schwensow et al.'s (2007) identification of MHC-DRB supertypes in fat-tailed dwarf lemurs seems premature
without knowledge about expression of the lemur DNA sequences. Only recently has it become clear that many rhesus macaque MHC-DRB sequences can be detected on the genomic, but not on the
cDNA level. de Groot et al. (2004) found that approximately 22% of macaque MHC-DRB sequences identified using genomic DNA were actually nonfunctional (that is, pseudogenes). A similar
comparison is now in order for fat-tailed dwarf lemurs. The identification of MHC-DRB genes in wild populations is increasingly popular, especially since functional polymorphism is
essentially restricted to exon 2, which is only 270 bp. Given the simplicity of identifying one single highly variable exon using almost any type of biological sample, it is likely that even
more research on these genes will be undertaken in future. In 2006, new molecular studies led to the discovery of dozens of previously unreported MHC-DRB sequences in species ranging from
bank voles to pandas. Unfortunately, the simplicity of PCR amplifying a single highly informative MHC-DRB exon from DNA can lead to misguided conclusions about protein expression. Schwensow
et al. (2007) have assumed that sequences without insertions, deletions or stop codons are functional (that is, form equals function). However, the MHC of most species is characterized by
duplication and inactivation of functional genes. Associations between MHC-DRB sequences and pathogen resistance, or susceptibility, require unambiguous identification of functional,
transcribed mRNA sequences. In these cases, function will follow form. Until then, conclusions that pathogen-driven selection drives MHC polymorphism based on form, but not function, will be
intriguing but premature. REFERENCES * de Groot N, Doxiadis GG, de Groot NG, Otting N, Heijmans C, Rouweler AJM _et al_. (2004). Genetic makeup of the DR region in rhesus macaques: gene
content, transcripts, and pseudogenes. _J Immunol_ 172: 6152–6157. Article CAS Google Scholar * Lohm J, Grahn M, Langefors A, Anderson O, Storset A, von Schantz T (2002). Experimental
evidence for major histocompatibility complex–allele-specific resistance to a bacterial infection. _Proc R Soc London B_ 269: 2029–2033. Article CAS Google Scholar * Paterson S, Wilson K,
Pemberton JM (1998). Major histocompatibility complex variation associated with juvenile survival and parasite resistance in a large unmanaged ungulate population. _Proc Nat Acad Sci USA_
95: 3714–3719. Article CAS Google Scholar * Penn DJ, Damajanovich K, Potts WK (2002). MHC heterozygosity confers a selective advantage against multiple-strain infections. _Proc Nat Acad
Sci USA_ 99: 11206–11264. Article Google Scholar * Piertney SB, Oliver MK (2006). The evolutionary ecology of the major histocompatibility complex. _Heredity_ 96: 7–21. Article CAS
Google Scholar * Schwensow N, Fietz J, Dausmann K, Sommer S (2007). Neutral versus adaptive genetic variation in parasite resistance: importance of MHC-supertypes in a free-ranging
population. _Heredity_, 99: 265–277. Article CAS Google Scholar * Wegner KM, Kalbe M, Kurtz J, Reusch TBH, Milinski M (2003). Parasite selection for immunogenetic optimality. _Science_
301: 1343. Article CAS Google Scholar EDITOR'S SUGGESTED READING * Nespolo RF (2007). A simple adaption to cycling selection: a complex population dynamic explained by a single-locus
Mendelian model for litter size. _Heredity_ 98: 63–64; advance online publication, 20 December 2006. Article CAS Google Scholar * Piertney SB, Oliver MK (2006). The evolutionary ecology
of the major histocompatibility complex. _Heredity_ 96: 7–21; advance online publication, 10 August 2005. Article CAS Google Scholar * Schaschl H, Wandeler P, Suchentrunk F, Obexer-Ruff
G, Goodman SJ (2006). Selection and recombination drive the evolution of MHC class II DRB diversity in ungulates. _Heredity_ 97: 427–437; advance online publication, 30 August 2006. Article
CAS Google Scholar * van Oosterhout C, Joyce DA, Cummings SM (2006). Evolution of MHC class IIB in the genome of wild and ornamental guppies, _Poecilia reticulata_. _Heredity_ 97:
111–118; advance online publication, 31 May 2006. Article CAS Google Scholar Download references AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Department of Biological Anthropology,
Primate Immunogenetics and Molecular Ecology Research Group, University of Cambridge, Downing Street, Cambridge, CB2 3DZ, UK L A Knapp Authors * L A Knapp View author publications You can
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Knapp, L. Selection on MHC: A matter of form over function. _Heredity_ 99, 241–242 (2007). https://doi.org/10.1038/sj.hdy.6800986 Download citation * Published: 30 May 2007 * Issue Date:
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